Significance of biopsy in SARS‐CoV‐2 mRNA vaccine‐associated myocarditis: Paving the way toward precision vaccinology

To the Editor,

We read with interest the report on significance of biopsy in SARS‐CoV‐2 mRNA vaccine‐induced myocarditis published in Pathology International. ¹ The authors described three patients who had similar histological findings of mild interstitial inflammatory infiltration by macrophages and few T‐cells without adjacency to cardiomyocyte necrosis. Eosinophils were either absent or rarely found. Based on the absence of viral genomes, the authors put the diagnosis of immune‐mediated myocarditis. Indeed, immune mRNA reactivity, sex‐related hormonal difference, quantity of mRNA antigen contained in each vaccine, and molecular mimicry between the spike protein of SARS‐CoV‐2 and cardiac self‐antigens have been also suggested as possible mechanisms of vaccine‐induced myocarditis. In this report, the diagnosis of myocarditis was based on the findings of cardiac magnetic resonance imaging which demonstrated positive nonischemic distribution pattern in early gadolinium enhancement images and myocardial edema on T2‐based images. In the medical literature, myocardial biopsies have been performed and reported in only a few patients due to the self‐limiting and mild course of the disease. However, in seven patients worldwide with myocarditis following SARS‐CoV‐2 mRNA vaccines, ² the biopsy in six patients, and the autopsy in the seventh patient demonstrated eosinophils and other inflammatory cells including lymphocytes. These reports were comprised of two from the United States, one from Israel, three from Italy, and a fatal case from Korea. Specifically, in the three patients from Italy, ³ there was extensive myocardial infiltration of degranulated eosinophils and elevation of serum cationic protein directly responsible for cardiomyocyte damage. Moreover, myocarditis after the first dose of SARS‐CoV‐2 mRNA vaccine has been reported in a 21‐year‐old man with previous history of atopic asthma in childhood and pollen and pet allergy. All of the above support the view that SARS‐CoV‐2 mRNA vaccine‐associated myocarditis seems similar to hypersensitivity or drug‐induced myocarditis ⁴ that is a subtype of eosinophilic myocarditis. Hypersensitivity myocarditis is particularly difficult to recognize clinically because the clinical features characteristic of a hypersensitivity reaction that are nonspecific skin rash, malaise, fever, and eosinophilia are absent in most cases. Indeed, the exact mechanism by which SARS‐CoV‐2 vaccines lead to myocarditis has not been completely elucidated, but the detection of even rare eosinophils denotes a hypersensitivity reaction. SARS‐CoV‐2 vaccines excipients such as polyethylene glycol (PEG) as part of the PEGylated lipid nanoparticles and trometamol or tromethamine that are ingredients of items used in everyday practice have been previously described as compounds with the potential to induce hypersensitivity. Creams, ointments, lotions, cosmetics, commonly used by young individuals, especially females, dental materials and even laxatives contain also PEG that is able to sensitize its users. The general population is sensitized to cosmetics or dental materials in 1%–5.4%. Alternative excipients have been suggested in vaccine manufacturing if vaccine component‐induced hypersensitivity is confirmed by systematic future investigations. Several authors have suggested that hypersensitivity to excipients constitutes risk to patients with allergy to PEG and these patients will await new vaccines containing different excipients The current recommendations presented in a recent position paper ⁵ will help to better understand the mechanisms of hypersensitivity reactions to SARS‐CoV‐2 vaccines, which fortunately remain very rare.

AUTHOR CONTRIBUTIONS

Acquisition and analysis of data: Nicholas G. Kounis, Ioanna Koniari, Virginia Mplani, Periklis Dousdampanis, Panagiotis Plotas. Drafting the manuscript or figure: Ioanna Koniari, Virginia Mplani.

CONFLICT OF INTEREST

The authors declare no conflict of interest.